Product Name: Boc-PEG6-Val-Cit-PAB-OH
Purity: 95%
Storage : Sealed storage, away from moisture
CAS.NO.: 2055024-53-6
CHEMICAl FORMULA: C38H66N6O13
Molar Mass: 814.96
SMILES: CC(C)[C@@H](C(=O)N[C@@H](CCCNC(=O)N)C(=O)NC1=CC=C(C=C1)CO)NC(=O)CCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C
IUPACNAME: tert-butyl N-[2-[2-[2-[2-[2-[2-[3-[[(2S)-1-[[(2S)-5-(carbamoylamino)-1-[4-(hydroxymethyl)anilino]-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate
INCHIKEY: BICDKJHWASHRHU-WEZIJMHWSA-N
INCHI: InChI=1S/C38H66N6O13/c1-28(2)33(35(48)43-31(7-6-13-40-36(39)49)34(47)42-30-10-8-29(27-45)9-11-30)44-32(46)12-15-51-17-19-53-21-23-55-25-26-56-24-22-54-20-18-52-16-14-41-37(50)57-38(3,4)5/h8-11,28,31,33,45H,6-7,12-27H2,1-5H3,(H,41,50)(H,42,47)(H,43,48)(H,44,46)(H3,39,40,49)/t31-,33-/m0/s1
Application: Boc-PEG6-Val-Cit-PAB-OH is a cleavable ADC linker used for the synthesis of antibody-drug conjugates in cancer research. It combines a PEG6 spacer to improve hydrophilicity and molecular flexibility, a Val-Cit dipeptide sequence for protease-sensitive cleavage, and a PAB self-immolative spacer to support efficient payload release after enzymatic processing. This linker is commonly used in targeted drug delivery studies where controlled intracellular release is critical for ADC performance. Boc-PEG6-Val-Cit-PAB-OH is valuable for ADC linker design, peptide synthesis, bioconjugation research, payload release evaluation, and development of antibody-based anticancer therapeutic platforms.
Current Research: Overview Boc-PEG6-Val-Cit-PAB-OH is a specialized ADC linker used in the synthesis of antibody-drug conjugates (ADCs). It contains several important structural modules commonly used in modern linker design, including a Boc protecting group, a PEG6 spacer, a Val-Cit cleavable peptide sequence, and a PAB-OH self-immolative spacer. Because of this modular architecture, Boc-PEG6-Val-Cit-PAB-OH is valuable in cancer research, especially in studies focused on targeted cytotoxic drug delivery and ADC linker-payload development. ADCs are designed to combine the selectivity of antibodies with the potency of cytotoxic small molecules. In a typical ADC, the antibody recognizes a tumor-associated antigen, while the payload kills target cells after internalization and release. The linker is the chemical bridge between these two components. Although it may appear to be only a connector, the linker strongly affects ADC stability, solubility, pharmacokinetics, intracellular release, therapeutic index, and off-target toxicity. Boc-PEG6-Val-Cit-PAB-OH is especially relevant because it combines hydrophilic PEG spacing with a protease-cleavable Val-Cit motif and a PAB-based self-immolative release unit. This design supports the development of ADC systems intended to remain stable during circulation and release the payload after internalization into tumor cells. Structural Design of Boc-PEG6-Val-Cit-PAB-OH Boc-PEG6-Val-Cit-PAB-OH is built from multiple functional components, each contributing to its role in ADC linker synthesis. The Boc group, or tert-butyloxycarbonyl group, is a protecting group commonly used in organic synthesis and peptide chemistry. It protects an amino functionality during stepwise linker construction. In ADC linker synthesis, protecting groups are essential because they allow chemists to control which reactive site participates in each reaction. The Boc group can later be removed under appropriate acidic conditions to expose the amine for further modification. The PEG6 spacer is a short polyethylene glycol chain containing six ethylene glycol units. PEG spacers are widely used in linker design because they increase hydrophilicity, improve aqueous compatibility, and may reduce aggregation caused by hydrophobic payloads. In ADC research, hydrophobic linker-payloads can negatively affect antibody conjugation, plasma behavior, and pharmacokinetics. Incorporating PEG units can help improve solubility and reduce nonspecific interactions. The Val-Cit sequence, composed of valine and citrulline, is one of the most widely studied cleavable peptide motifs in ADC development. Val-Cit linkers are designed to be cleaved by intracellular proteases, especially lysosomal cathepsins, after ADC internalization. This allows the ADC to remain relatively stable outside the cell while enabling payload release inside target cancer cells. The PAB-OH group, related to p-aminobenzyl alcohol, functions as a self-immolative spacer. After enzymatic cleavage of the Val-Cit peptide, the PAB unit can undergo a self-immolative breakdown process, helping release the attached payload in its active or more active form. This makes PAB-based linkers highly useful for payloads that require clean release from the linker structure. Role in Antibody-Drug Conjugate Synthesis Boc-PEG6-Val-Cit-PAB-OH can be used as a linker intermediate for synthesizing ADCs. It is not the final ADC by itself, but rather a modular component used to build linker-payload structures that can later be attached to antibodies or other targeting molecules. In ADC synthesis, linker intermediates must be compatible with several requirements. They need to support efficient coupling to the payload, allow conjugation to the antibody, maintain stability during purification and storage, and enable release under the desired intracellular conditions. Boc-PEG6-Val-Cit-PAB-OH contributes to these requirements by combining a cleavable peptide sequence with a solubilizing PEG spacer and a self-immolative PAB unit. A typical ADC linker-payload construction workflow may involve attaching a cytotoxic payload to the PAB-OH portion or a downstream derivative, modifying or deprotecting the Boc-protected group, and installing a functional antibody-conjugation handle. Depending on the synthetic strategy, the final linker-payload may be connected to antibody lysines, cysteines, engineered residues, or site-specific conjugation groups. Importance of the Val-Cit Cleavable Peptide Motif The Val-Cit motif is a major feature of Boc-PEG6-Val-Cit-PAB-OH. In ADC research, Val-Cit is widely used because it can be cleaved in lysosomal environments after ADC internalization. This cleavage mechanism supports selective payload release in target cells. After an ADC binds to a tumor-associated antigen, it is often internalized through receptor-mediated endocytosis. The ADC then traffics through endosomes and lysosomes, where proteolytic enzymes can process the linker. For Val-Cit-containing linkers, cathepsin-mediated cleavage removes the peptide trigger, allowing the self-immolative PAB unit to release the payload. This mechanism is valuable because it separates systemic stability from intracellular activation. Ideally, the ADC remains intact in plasma, reducing premature payload release and systemic toxicity. Once inside antigen-positive cancer cells, the linker is cleaved and the payload is released, producing localized cytotoxic activity. Because payloads used in ADCs can be extremely potent, this balance is critical. Even small amounts of premature release can increase toxicity, while insufficient intracellular release can reduce antitumor efficacy. Boc-PEG6-Val-Cit-PAB-OH is therefore relevant to linker optimization studies focused on improving the therapeutic index of ADC candidates. Function of the PEG6 Spacer The PEG6 spacer is another important component of Boc-PEG6-Val-Cit-PAB-OH. PEGylated linkers are used to improve the physicochemical properties of linker-payload intermediates and final ADCs. Many ADC payloads are hydrophobic, and hydrophobicity can cause aggregation, poor solubility, rapid clearance, or unfavorable distribution. A PEG6 spacer increases hydrophilicity and can help improve linker-payload handling during synthesis. It may also reduce steric hindrance between the antibody and the cleavable peptide region, allowing better protease accessibility after internalization. In some ADC designs, PEG spacers can also influence drug-to-antibody ratio tolerance by reducing aggregation risks associated with higher payload loading. The length of the PEG spacer matters. PEG6 provides a moderate hydrophilic spacer that can improve solubility without excessively increasing linker length or molecular weight. This makes Boc-PEG6-Val-Cit-PAB-OH suitable for research where linker flexibility, aqueous compatibility, and intracellular release behavior must be balanced. PAB-OH as a Self-Immolative Spacer The PAB-OH unit helps translate peptide cleavage into payload release. In many cleavable ADC linkers, enzymatic cleavage of the peptide alone does not automatically generate the desired free drug. A self-immolative spacer solves this issue by undergoing spontaneous decomposition after the peptide trigger is removed. In Val-Cit-PAB systems, cleavage of the Val-Cit sequence exposes the PAB spacer, which then undergoes a 1,6-elimination-type process. This can release the payload from the linker in a controlled way. The PAB spacer is therefore an important component in ADC linker systems where the payload requires release from a carbamate, carbonate, or related linkage. For Boc-PEG6-Val-Cit-PAB-OH, the PAB-OH portion provides a functional platform for further payload attachment or linker-payload development. This makes the compound useful for researchers designing ADCs with controlled intracellular drug release. Applications in Cancer Research Boc-PEG6-Val-Cit-PAB-OH can be used in cancer research through its role in ADC linker synthesis. ADCs are among the most important targeted drug delivery platforms in oncology because they allow potent cytotoxic agents to be directed toward tumor cells expressing specific antigens. Potential research applications include: ADC linker-payload synthesis, where Boc-PEG6-Val-Cit-PAB-OH is used to construct cleavable linker-payload intermediates. Targeted anticancer drug delivery, where Val-Cit-PAB-based linkers support intracellular payload release after antibody-mediated uptake. Linker optimization studies, where PEGylated Val-Cit-PAB linkers are compared with non-PEGylated or alternative peptide linkers. Payload release assays, where researchers evaluate enzymatic cleavage, self-immolation, and drug liberation under lysosomal or protease-rich conditions. ADC stability evaluation, where linker behavior is assessed in plasma, serum, buffer systems, and cell-based environments. Structure-activity relationship research, where the effects of PEG spacer length, peptide motif, and self-immolative chemistry are studied in relation to ADC activity and safety. Research Considerations When using Boc-PEG6-Val-Cit-PAB-OH, researchers should consider several experimental and design factors. First, the compound is a linker intermediate, not a complete ADC. Its performance depends on the final antibody, payload, conjugation chemistry, drug-to-antibody ratio, antigen expression level, and internalization pathway. Second, Val-Cit cleavage should be experimentally validated. Although Val-Cit is a well-established cleavable motif, cleavage efficiency depends on steric accessibility, linker-payload structure, protease expression, and intracellular trafficking. Third, PEGylation can improve solubility but may also influence pharmacokinetics, linker spacing, and payload release. The PEG6 spacer should be evaluated in the context of the full ADC design. Fourth, PAB-based self-immolation depends on the downstream linkage to the payload. The payload attachment chemistry must be compatible with the intended release mechanism. Fifth, analytical characterization is essential. Researchers may use LC-MS, HPLC, NMR, peptide mapping, hydrophobic interaction chromatography, size-exclusion chromatography, drug-to-antibody ratio analysis, plasma stability testing, and cell-based cytotoxicity assays to evaluate linker-payload and ADC quality. Future Research Directions As ADC technology continues to advance, linker design is becoming increasingly sophisticated. Researchers are optimizing not only payload potency and antibody specificity, but also linker solubility, cleavage selectivity, release kinetics, and conjugation homogeneity. Boc-PEG6-Val-Cit-PAB-OH reflects this trend by combining a PEGylated spacer with a classic cleavable peptide motif and a self-immolative release group. Future studies may explore Boc-PEG6-Val-Cit-PAB-OH-derived linkers with different payload classes, including tubulin inhibitors, DNA-damaging agents, topoisomerase inhibitors, immune-modulating payloads, and targeted protein degradation agents. Researchers may also compare PEG6-containing linkers with PEG2, PEG4, PEG8, or non-PEG linkers to determine how spacer length affects ADC solubility, aggregation, plasma stability, and antitumor activity. In addition, next-generation ADC platforms increasingly use site-specific conjugation to improve homogeneity and control drug-to-antibody ratio. Linkers based on Boc-PEG6-Val-Cit-PAB-OH may be adapted to such strategies by incorporating suitable conjugation handles after deprotection and functionalization. Conclusion Boc-PEG6-Val-Cit-PAB-OH is an important ADC linker intermediate used for synthesizing antibody-drug conjugates. Its structure combines a Boc-protected functional group, a hydrophilic PEG6 spacer, a cleavable Val-Cit peptide motif, and a PAB-OH self-immolative spacer. This modular design makes it useful for constructing cleavable linker-payload systems for cancer research. In ADC development, Boc-PEG6-Val-Cit-PAB-OH supports key linker functions, including improved solubility, intracellular protease-responsive cleavage, and controlled payload release. As targeted oncology research continues to expand, PEGylated Val-Cit-PAB linkers like Boc-PEG6-Val-Cit-PAB-OH will remain valuable tools for developing optimized ADCs with improved stability, selectivity, and anticancer activity.
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